Over 90% of women with ovarian cancer confined to the ovary survive five years, but the majority of all cases are diagnosed at a later stage, and few of them survive five years. That strong association between stage and survival suggests that detecting ovarian cancer early could dramatically reduce mortality, and it has been our goal to identify and develop strategies to accomplish this. Presently the only ovarian cancer early detection strategy uses a single tumor marker, CA 125, in conjunction with imaging technologies, 1-3 and there is a consensus that improvements are needed, in part because CA 125 is insensitive to early stage disease, and imaging is too non specific on its own. In our current early detection project we have sought to define a systematic approach to identify many novel markers that could improve disease detection when used with CA 125, and we have made substantial progress since our first efforts to discover new markers. At present we are completing a cooperative blinded biomarker study to evaluate our markers along side markers from several research collaborators around the world. It is our goal to identify which of them complement CA 125, and our preliminary results are promising. We now propose to further evaluate some of these biomarkers in retrospective and prospective screening studies. The success of our research plan relies on our theoretically sound but practical research methods and our valuable serum and data repositories, which allow us the unique opportunity to estimate the sensitivity and pre-clinical period of our markers and marker panel. With this information we intend to select a panel of screening markers that will achieve the earliest detection possible, and then pilot them prospectively in a screening research trial in a population of BRCA mutation carriers, and for use as a diagnostic test. Moreover, because we and others continue to exploit modern biotechnology to identify other putative early detection and diagnostic markers, we will continue to improve our marker panel by developing assays for novel targets and evaluating them, along with our collaborators' markers, in a continuing blinded evaluation study. At the end of our project we intend to have identified and characterized a panel of high performing novel markers to the point where full clinical evaluation is warranted.